This invention relates to a pharmaceutical combination of a selective estrogen receptor modulator (SERM) and PGE2 or a pharmaceutically acceptable salt thereof that stimulates bone formation, increases bone mass and enhances bone restoration effects of PGE2. The invention also relates to kits containing such combinations and the use of such combinations to treat musculoskeletal frailty, including osteoporosis, osteoporotic fracture, low bone mass, frailty and the like in mammals, including humans. In particular, this invention relates to a combination of (-)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydr onaphthalene-2-ol or a pharmaceutically acceptable salt thereof and PGE2 or a pharmaceutically acceptable salt thereof, kits containing such a combination and the use of such a combination to treat musculoskeletal frailty, including osteoporosis, osteoporotic fracture, low bone mass, frailty and the like in mammals, including humans.
Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the U.S., the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually. Hip fractures are the most serious, with 5-20% of patients dying within one year, and over 50% of survivors being incapacitated.
The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population. Worldwide fracture incidence is forecast to increase three-fold over the next 60 years, and one study estimates that there will be 4.5 million hip fractures worldwide in 2050.
Although both men and women are susceptible to musculoskeletal frailty, including osteoporosis, women are at greater risk of osteoporosis than men. Women experience a sharp acceleration of bone loss immediately following menopause. Other factors that increase bone loss leading to osteoporosis include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake.
Estrogen is the agent of choice in preventing osteoporosis or post menopausal bone loss in women. In addition, Black, et al. in EP 0605193A1 report that estrogen, particularly when taken orally, lowers plasma levels of LDL and raises those of the beneficial high density lipoproteins (HDL's). Long-term estrogen therapy, however, has been implicated in a variety of disorders, including an increase in the risk of uterine cancer, endometrial cancer and possibly breast cancer, causing many women to either avoid this treatment or take the medication for only a short period of time. Although the risk of endometrial cancer is thought to be reduced by a concurrent use of a progesterone, there is still concern about possible increased risk of breast cancer with the use of estrogen. Recently suggested therapeutic regimens, which seek to lessen the cancer risk, such as administering combinations of progesterone and estrogen, cause the patient to experience unacceptable bleeding. Furthermore, combining progesterone with estrogen seems to blunt the serum cholesterol lowering effects of estrogen. The significant undesirable side effects associated with estrogen therapy support the need to develop alternative therapies for osteoporosis that have the desirable beneficial effect on serum LDL but do not cause undesirable side effects.
Recently, a number of selective estrogen receptor modulators have been proposed for treatment of osteoporosis. It has been reported (Osteoporosis Conference Scrip No. 1812/13 Apr. 16/20, 1993, p. 29) that raloxifene, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thi ophene, mimics the favorable action of estrogen on bone and lipids but, unlike estrogen, has minimal uterine stimulatory effect. [Black, L. J. et al., Raloxifene (LY139481 Hcl) Prevents Bone Loss and Reduces Serum Cholesterol Without Causing Uterine Hypertrophy in Ovariectomized Rats, J. Clin. Invest., 1994, 93:63-69 and Delmas, P. D. et al., Effects of Raloxifene on Bone Mineral Density, Serum Cholesterol Concentration, and Uterine Endometrium in Postmenopausal Women, New England Journal of Medicine, 1997, 337:1641-1647].
Agents such as droloxifene, U.S. Pat. No. 5,254,595, prevent bone loss and thereby reduce the risk of fracture without estrogen's side effects. However, estrogen and estrogen agonists alone are only expected to reduce the fracture risk by about 50% leaving approximately 50% of osteopenic women still at risk for an osteoporotic fracture.
Commonly assigned U.S. Pat. No. 5,552,412, which is incorporated herein by reference, discloses SERM compounds of the formula ##STR1##
wherein the variables are defined as set forth therein. (-)-Cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8,-tetrahyd ronaphthalene-2-ol is an orally active, highly potent SERM which prevents bone loss, decreases total serum cholesterol, and does not have estrogen-like uterine stimulating effects in OVX rats.
PGE2 restores bone mass by stimulating both bone formation and bone resorption. However, in ovariectomized rat skeleton, PGE2 favors bone formation over bone resorption.
Tang et al., Restoring and Maintaining Bone in Osteogenic Female Rat Skeleton: I. Changes in Bone Mass and Structure, J. Bone Mineral Research 7 (9), p1093-1104, 1992 discloses data for the lose, restore and maintain (LRM) concept, a practical approach for reversing existing osteoporosis. The LRM concept uses anabolic agents to restore bone mass and architecture (+ phase) and then switches to an agent with the established ability to maintain bone mass, to keep the new bone (+/- phase). The rat study utilized PGE.sub.2 and risedronate, a bisphosphonate, to show that most of the new cancellous and cortical bone induced by PGE.sub.2 can be maintained for at least 60 days after discontinuing PGE.sub.2 by administering risedronate.
Shen et al., Effects of Reciprocal Treatment with Estrogen and Estrogen plus Parathyroid Hormone on Bone Structure and Strength in Ovariectomized Rats, J. Clinical Investigation, 1995, 96:2331-2338 discloses data for the combination and/or sequential use of anti-resorptive agents and anabolic agents for the treatment of osteoporosis.